A series of distantly related Mus species have been tested for their ability to interbreed with laboratory strains and to produce viable, fertile hybrids. Among these species, M. spretus has proved to be extremely valuable as a parental resource stock that is highly diverged from laboratory mice but still viable in F1 hybrid combinations. In these hybrids, the females are fertile and they can be backcrossed with either parental genotype. By contrast, the hybrid males are sterile with little or no evidence of spermatogenesis beyond metaphase I of meiosis. Preliminary work indicates that a failure of X-Y chromosome pairing is a prominent feature of the meiotic prophase of these hybrids and that it may be causal of the sterile phenotype. Taken together, the initial work indicates that normal X-Y pairing is an essential requisite for the progression of meiosis beyond metaphase I and that divergent Mus species may lack sufficient sequence homology in the X-Y pairing region to allow this interaction to occur. Thus, the sterile hybrid males may provide important information about the regulation of meiosis and spermatogenesis. From an evolutionary perspective, the divergence of X-Y pairing regions may be an important feature in the process of speciation. This proposal outlines specific aims to address the genetic basis of male sterility in mouse species hybrids including the role of X-Y chromosome pairing in this phenotype and an analysis of the molecular basis for the pairing failure. The program also retains a strong research resource combined with a specific set of research questions that use a broad sampling of the mouse gene pool as special research resources. The research resources supported by this grant include 1) a diverse set of wild-derived, laboratory maintained outbred Mus species, 2) a series of congenic strains carrying wild-derived alleles for a variety of different genes, 3) rare inbred strains and mutant stocks that are critical to the broader research interests of several investigators in our department and 4) a small series of mutants recovered from ENU mutagenesis studies conducted in our program. Thus a central theme of the proposal is the continuation of this resource and an outline program to improve its value to us and the broader community of mouse genetics and medical research.